B7-H6 is a member of the B7 family, which includes ligands (B7-1 and B7-2) for the T cell costimulatory receptor CD28 and the coinhibitory receptor CTLA-4, as well as ligands (PD-L1 and PD-L2) for the T cell coinhibitory receptor PD-1. Like all known B7 family members, B7-H6 comprises two Ig domains with adjacent phase 1 introns in the extracellular region. Importantly, B7-H6 was not detected in normal human tissues but was selectively expressed on a variety of human tumor cell lines, including T and B lymphomas, melanomas, and carcinomas (Brandt C S et al., 2009, J. Exp. Med., 206:1495). Furthermore, B7-H6 expression on tumor cells triggered NKp30-specific NK cell cytotoxicity and cytokine secretion. Thus, B7-H6 functions as a tumor-induced self-molecule that alerts innate immunity to cellular transformation via its interaction with the activating receptor NKp30 (Brandt C S et al., 2009, J. Exp. Med., 206:1495). B7-H6 transcripts have not been detected in most normal adult tissues, consistent with the absence of the protein on circulating cells isolated from healthy individuals.
As used herein, the term “MICA” refers to the MHC class I chain-related protein A encoded by the MICA gene (Gene ID: 100507436). As used herein, the term “MICB” refers to the MHC class I chain-related protein B encoded by the MICB gene (Gene ID: 4277). MICA and MICB are NKG2D ligands as defined above. MICA and MICB are highly related, sharing 85% amino acid identity. The term “MIC” refers to MICA and/or MICB.
“MIC” is a heavily glycosylated protein which is a ligand for the NKG2D type II receptor. Binding of the ligand activates the cytolytic response of natural killer (NK) cells, CD8 alpha beta T cells, and gamma delta T cells which express the receptor. This protein is stress-induced and is similar to MHC class I molecules.
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. GISTs are thought to originate from the neoplastic transformation of the interstitial cells of Cajal, the intestinal pacemaker cells. The true incidence of GISTs remains unknown, but experience from clinical trials suggests an incidence of 4500-6000 new cases per year in the United States. The median age at diagnosis is approximately 58 years.
Historically, GISTs have been targeted by the three traditional cancer therapeutic modalities: surgery, chemotherapy, and radiotherapy. Surgery is effective for patients with resectable disease, but disease may recur in as many as 50% of individuals. Chemotherapy and radiotherapy have shown little efficacy (Joensuu H et al., 2002, Lancet Oncol, 3: 655). A major breakthrough occurred in 1998 with the discovery of gain-of-function mutations in the KIT oncogene in GISTs (Hirota S et al., 1998, Science, 279: 577). KIT encodes the transmembrane KIT receptor tyrosine kinase (CD117) that, when activated via binding by its ligand, regulates the intracellular signal transduction process. Constitutive tyrosine kinase activation by mutation results in unregulated cell growth and malignant transformation. More than 90% of GISTs harbour activating KIT mutations (Rubin B P et al., 2001, Cancer Res, 61: 8118). These mutations commonly occur in exon 11 (juxtamembrane domain) in 57-71% of cases, exon 9 (extracellular domain) in 10-18% of cases, exon 13 (tyrosine kinase domain I) in 1-4% of cases, and exon 17 (tyrosine kinase domain II) in 1-4% of cases (Raut C P et al., 2007, Curr Opin Gastroenterol, 23: 149). Approximately 35% of GISTs lacking KIT mutations have activating mutations in a gene encoding a related receptor tyrosine kinase, the platelet-derived growth factor receptor a (PDGFRA) (Heinrich M C et al., 2003, Science, 299: 708). PDGFRA mutations have been identified in exon 12 (1-2% of GISTs), exon 18 (2-6%), and exon 14 (<1%) (Corless C L et al., 2005, J Clin Oncol, 23: 5357). Identification of KIT and PDGFRA mutations led to the development of specific targeted therapies with tyrosine kinase inhibitors (TKIs). Therapy with the TKIs imatinib mesylate (STI571, Gleevec-Novartis) and sunitinib malate (SU11248, Sutent-Pfizer) is effective for unresectable, metastatic, and recurrent disease (Heinrich M C et al., 2003, J Clin Oncol, 21: 4342). Imatinib selectively inhibits several tyrosine kinases including KIT, PDGFRA, and ABL. Data from a phase II imatinib trial revealed that mutational status of KIT was the most important factor predictive of clinical response to imatinib (Heinrich M C et al., 2003, J Clin Oncol, 21: 4342). Patients with GISTs expressing exon 11 KIT mutants who received imatinib had a substantially higher partial response rate, longer median survival, and less likelihood of progressing than those with GISTs expressing wild-type or exon 9 KIT mutants. Imatinib is a dramatically effective agent, but the duration of its benefits is finite. The second targeted tyrosine kinase inhibitor, sunitinib malate, has been approved for the treatment of imatinib-resistant GISTs after recent encouraging results (Rubin B P et al., 2007, Lancet, 369: 1731). However, as explained previously, drug resistance is an increasingly more common phenomenon (Van Glabbeke M et al., 2005, J Clin Oncol, 23: 5795).
Renal cell carcinoma (RCC, also known as hypernephroma) is a renal cancer that originates in the lining of the proximal convoluted tubule, the very small tubes in the kidney that filter the blood and remove waste products. RCC is the most common type of kidney cancer in adults, responsible for approximately 80% of cases (Mulders P F et al., 2008, Ned Tijdschr Geneeskd, 152: 376). It is also known to be the most lethal of all the genitourinary tumors. Initial treatment is most commonly a radical or partial nephrectomy and remains the mainstay of curative treatment (Rini B I et al., 2008, Curr Opin Oncol, 20: 300). Where the tumor is confined to the renal parenchyma, the 5-year survival rate is 60-70%, but this is lowered considerably where metastases have spread. It is relatively resistant to radiation therapy and chemotherapy, although some cases respond to immunotherapy. Targeted cancer therapies such as sunitinib, temsirolimus, bevacizumab, interferon-alpha, and sorafenib have improved the outlook for RCC (progression-free survival), although they have not yet demonstrated improved survival.
Whatever the nature of the cancer, the accurate selection of the patients capable of responding to a particular chemotherapy is a solution for them to receive the most appropriate therapy as soon as possible and typically as soon as they are diagnosed.